This project is designed to study by morphologic, immunologic and virologic methods the pathogenesis of central nervous system (CNS) infection and demyelination in the trigeminal root entry zone after corneal inoculation of mice with herpes simplex virus Type I (HSV). The experimental model used produces only CNS demyelination associated with a mononuclear cell response four to seven days after corneal infection of mice with HSV. I. Most studies suggest that the major transport of HSV from the periphery to the CNS is through axonal transport. How virus enters peripheral axons has not been well delineated. Ultrastructural analysis of corneal infection in mice with peroxidase labelling of viral antigens will help clarify how virus enters and is transported within axons. These "in vivo" studies will be combined with "in vitro" infection of dorsal root ganglion-spinal cord cultures to study how HSV enters and is transported in the nervous system. II. The initial cell responding in the CNS after corneal infection are macrophages. In immune competent animals, T cells appear by 5 days after infection. It is not known what subsets of T cells respond to the infection nor the role of B cells in the CNS. Immunoperoxidase studies with monoclonal antibodies would characterize the types of cells responding in the CNS after peripheral inoculation of HSV. III. Oligodendroglial infection occurs but the extent and timing of infection is not known. In order to evaluate the significance of oligodendroglial infection and its possible association with early myelin breakdown, specific labelling of oligodendrocytes with anti-galactocerebroside sera in infected animals will be done. IV. Although peripheral inoculation of HSV on the cornea or foot pad causes infection of Schwann cells, no PSN demyelination occurs. Preliminary studies show that direct injection of the sciatic nerve with small amounts of HSV causes PNS demyelination. This would suggest that extracellular virus may have a role in myelin disruption. These experiments are designed to further analyze the role of extracellular HSV in demyelination. V. The role of HSV as an antigenic stimulus in the CNS will be analyzed with transfer studies of HSV stimulated T cells to Nude mice. T cells stimulated "in vivo" to HSV in Balb/c mice will be further stimulated "in vitro" and then injected into corneally infected Nude mice.